Pathological conditions can arise from, and can cause changes in surface tension values of air/liquid interfaces resident upon tissue surfaces, especially epithelial surface tissues, of and within various organs of mammalian anatomy. The naturally occurring “surfactant system” secreted upon the epithelial lining of the lung which is deficient in cases of R.D.S. is known to be comprised of a complex mixture of lipids, proteins and carbohydrates (as described in: Surfactants and the Lining of the Lung, The John Hopkinds University Press, Baltimore, 1988).
The prime function of the surfactant system is to stabilize the alveoli and associated small airways against collapse by decreasing the surface tension at the air/liquid interface. It is now believed that the action of the phospholipid component of the surfactant system is the principal source of the powerful surface tension reduction effect of the naturally occurring surfactant system of the lung. More specifically, it is known that the fully saturated diacylphospholipids, principally dipalmitoyl phosphatidylcholine (DPPC), provide liquid balance and anti-collapse properties to the lung's epithelial lining and alveoli. In addition to DPPC, spreading agents, also found within the naturally occurring surfactant system, assist DPPC in rapidly forming a uniform spread film on the air/liquid surfaces of the lung. Such spreading agents include cholesteryl esters such as, for example, cholesteryl palmitate (CP); phospholipids such as, for example, diacylophosphatidylglycerols (PG), diacylphosphatidylethanolamines (PE), diacylphosphatidylserines (PS), diacylphosphatidylinositols (PI), sphingomelin (Sph) and Cardiolipin (Card) and virtually and other phospholipid, and the lysophospholipids; or any of the plasmalogens, dialklylphospholipids, phosphonolipids; carbohydrates and proteins, such as, for example, albumin, pulmonary surfactant proteins A, B, C and D. The naturally occurring surfactant system is further described in U.S. Pat. No. 5,306,483.
DPPC has been administered to infants with respiratory distress syndrome as a therapeutic measure in order to restore deficient or low levels of natural surfactant. For this purpose, DPPC has been administered by means of an aqueous aerosol generator (utilized with an incubator in which the infant resided during treatment). Endotracheal administration has also been utilized. DPPC therapy has been typified as utilizing natural surfactants (harvested from porcine or bovine lungs), or artificial, commercially synthesized compounds.
It has also heretofore been disclosed to utilize therapeutic agents, in combination with surfactant/spreading agents to effectively administer drug therapy uniformly throughout the epithelial lining of the lung. U.S. Pat. No. 5,306,483 (the “'483 patent”) discloses a process to prepare lipid crystalline figures in fluorocarbon propellants for the delivery of therapeutically active substances which form amorphous fluids on delivery at the air/liquid interface of the lung and which can be utilized as an effective drug delivery system. More specifically, said patent discloses a process comprising (a) preparing a mixture of one or more lipids of the group of phospholipids known as phosphatidylcholines and one or more spreading agents, in powder form and a therapeutically active substance and one or more fluorocarbon propellants, said lipids, spreading agents and therapeutically active substances being insoluble in the propellants; and (b) evaporating the propellants from the mixture. The '483 patent teaches the combination of dipalmitoyl phosphatidylcholine (DPPC) or any of the other fully saturated Acyl chain phospholipids, 80.0 to 99.5% by weight, and other spreading agents, for example, phospholipids such as, but not limited to PG, PE, PS, PI, lysophospholipids, plasmalogens, dialkylphospholipids, diether phosphonolipids, Cardiolipin, sphingomyelin, 0.5 to 20.0% weight; neutral lipids like cholesteryl esters such as, but no limited to, cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate, 0.5 to 10% by weight, carbohydrates, such as, but not limited to, glucose, fructose, galactose, pneumogalactan, dextrose, 0.5 to 10% by weight; and proteins such as, but not limited to albumin, pulmonary surfactant specific proteins A, B, C, and D 0.5 to 10% by weight, yielding lipid-crystalline structures in fluorocarbon (both chloro- and hydrofluorocarbon) propellants in which therapeutically active agents, drugs and other materials can be carried into the lungs after release from and through metered dose nebulizer. The spreading agents referred to in the '483 patent are compounds such as the above-described phospholipids, lysophospholipids, plasmalogens, dialklyphospholipids, phosphonolipids, carbohydrates and proteins. The function of the spreading agent is to assist DPPC, or other phospholipids such as, for example, DPPG, in rapidly adsorbing and forming a spread film upon the air/liquid surfaces of the lungs. In addition, the '483 patent also discloses a process for preparing such lipid crystalline figures in fluorocarbon propellants without a therapeutically active substance for use as a tear (as for the eye).
The outer air canal, or, as it is also known, the external auditory canal, is lined with epithelium. It is susceptible to the same type of skin diseases as effect skin in other parts of the mammalian anatomy including, for example, eczema and psoriasis. Glands within the canal secrete a waxy exudate known as cerumen which aids in trapping air born debris as well as acidifying the epithelial surface. Such acidification, in turn, minimizes the overgrowth of bacteria. However, upon exposure to copious amounts of exogenous water such as, for instance, during swimming, the epithelial lining may become more alkaline, leading to an increased growth and over-growth in bacteria. Strains of Staphylococcus, Streptococcus and Psuedomonas species often capitalize on such alkaline conditions leading to infection and the resultant inflammatory response characteristic of infective otitis externa—immune mediated swelling, redness, heat and pain, often associated with a discharge which contains white blood cells—. Discomfort caused by this condition ranges from a slight itch to severe pain. Temporary deafness may also result as swelling and discharge physically closes off the ear canal and prevents conduction of ambient sound to the ear drum. In addition to bacteria, fungal and viral organisms are also causative of infective otitis externa. Non-microbial antigenic material is causative of another form otitis externa—specifically, allergic otitis externa—.
The cerumen exudate, normally secreted upon the epithelial tissue lining the external auditory canal, imparts a particularly high surface tension thereto which is useful in preventing foreign matter from reaching the tympanic membrane and effecting the middle and inner ear. Inflammatory by-products, discussed in greater detail below, can further increase such surface tension. Increased surface tension is an important factor in both the symptoms and treatment of otitis externa. The epithelial wall lining the outer ear canal exhibits greater than usual surface tension during otitis externa due to the secretion thereupon of proteinaceous inflammatory waste material resulting from the lysis, phagocytosis and necrosis of antigenic material. In addition, cerumen production increases in response to inflammation of the epithelial lining of the external auditory canal. This material is highly viscous in nature. Furthermore, and also as a result of the inflammatory process, the epithelium may become extremely swollen thereby causing proximal and/or opposing walls of the auditory canal to come into close approximation of one another. As such exudate laden walls come into close proximity, the high surface tension thereof may cause the adhesion of such opposing and/or proximal walls so as to completely close off the external auditory canal.
The closure of the external auditory canal is highly problematic in that both the treatment as well as the symptoms of otitis externa are negatively effected since such closure: i. blocks the transmission of sound to the middle ear; ii may result in painful increased pressure against the ear drum; and iii. inhibits and resists the application of medicine—through the external auditory meatus—to the effected tissues. In addition, and even in the absence of canal closure, the afore-mentioned increased surface tensions resident upon the epithelial lining of the outer ear canal, tends to inhibit uniform and/or effective application of therapeutic agents effective in the treatment of the inflammatory condition as well as such agents effective in treatment of the underlying causative antigenic triggers.
As discussed in greater detail below, antigenic material can induce, through the inflammatory response, a marked increase in cerumen secretion from the epithelial lining of the outer ear canal. In addition, the inflammatory response to increased quantities of antigenic material quite often results in increased permeability of capillaries located close to the epithelial lining. Such increased permeability results in a localized edema or swelling of the epithelial lining of the external ear canal discussed above. Such edema is the direct result, in part, of various components of blood seeping into the interstitial epithelial spaces including migration of antibody laden white cells therein where pmns may complex with the antigenic trigger of the inflammatory reaction. A substantial quantity of the resulting waste material is often excreted onto the epithelial lining of the cerumen covered external auditory canal wherein said material, highly viscous in nature, greatly elevates there surface tension of the epithelial lining.
The localized edema—observed as substantial swelling of the epithelial walls of the outer ear canal—tends to narrow this conduit between the lateral terminus of the external auditory meatus and the tympanic membrane. At the same time, the proteinaceous remnants of inflammatory phagocytosis, lysis and enzymatic destruction, discussed above, combine with the increased quantity of cerumen to form a coating upon the epithelial lining of the outer ear canal with substantially increased surface tension values.
For example, during the course of a common example of otitis externa, often referred to as “swimmer's ear,” the out ear canal is filled with water. The effect of the water upon the normally acidic epithelial lining of the external auditory canal, is to overcome the bacteriostatic low ph conditions provided by healthy cerumen production, and cause alkalinization. Rising ph level of the outer canal allow bacteria, such as, for example species of staphylococcus, streptococcus and pseudomonas to multiply, overwhelm, and invade the epithelium. Water exposure may also act as a vector in introducing toxic and/or irritating chemicals into the ear canal wherein such chemicals act as antigens and/or break down the integrity of the epithelial lining of the external canal and allow bacterial, fungal and other microbial agents into the epithelial tissue.
Within the epithelium, the antigenic proteins of such bacteria—or in other cases, fungal, viral or other antigenic material—may come into contact with macrophages present in such tissue. Such macrophages may induce an initial immune response by presenting such antigenic material to T-lymphocytes such as, for example, a CD4+ T lymphocyte. Upon such presentation, CD4+ lymphocytes respond, in part, by releasing a multitude of interleukins and cytokines which, in turn, promote the production of increased quantities of cerumen. In addition, presentation of antigen to lymphocyte leads to a cascade of inflammatory activity wherein pmns, with activated antibody, leach out of capillaries which have been made permeable thereto by histamine, into the epithelium wherein they complex with antigen for phagcytotic, lytic and macrophagic activities. The release of arachidonic acid from such activated mast cells, macrophages and pmns may lead to, for example, the production of luekotrienes. Luekotrienes, have inflammatory effects similar to histamine. However, luekotrienes effect such chemotaxis and enhanced mucous production to a far greater degree than histamine.
Two inflammatory effects, localized edema and increased exudate surface tension act, in concert, to promote and enable the above-described attraction and adhesion of proximal epithelial surfaces to one another leading to increased blockage of the outer ear canal. However, it is the high surface tension properties of the secretions that allow and promote proximal inflamed tissues of the outer ear to remain adherent upon each other. In addition, prior to the afore-mentioned inflammatory response, it is often the effect of water: i. causing alkalinization induced bacterial overgrowth—, ii. acting as a vector for chemical toxins/irritants, or iii. directly effect in interrupting the epithelial barrier of the outer ear canal that allows antigen contact to initiate the above-described inflammatory cascade that comprises otitis externa.
In the past, otitis externa has been treated with the topical application of therapeutic agents demonstrating antimicrobial activity as well as anti-inflammatory action. Broad spectrum topically effective antibiotic otic suspensions containing antibacterial agents such as, for example, neomycin sulfate, colistin sulfate, polymyxin b, or combinations thereof, all broad spectrum in effect, have been utilized to destroy causative bacteria. Anti-mycotic topically acting agents such as, for example, nystatin and clotrimazole have been employed to destroy underlying fungal disease. In addition, the anti-viral agent acyclovir has been utilized to treat viral based otits externa including herpes zoster.
Anti-inflammatory agents, often included in the above-identified topically acting suspensions, have been employed to control the inflammatory process of otits externa including, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate. Most often, the above-described therapeutically active agents are utilized in combination to treat both the causative, triggering disorder, e.g. bacterial infection, as well as the inflammatory process itself. They are also most often utilized in drop form for topical administration to the effected ear. In order to enhance a more uniform delivery of such medications to the epithelial lining of the outer ear canal, wicks, comprised of absorbent material such as, for example, cotton, are utilized to draw the suspensions into the ear canal for as complete an administration as possible. However, due to the above-described exudate present in purulent forms of otitis externa, and the cerumen present in virtually all inflammatory conditions, high surface tension within the canal is resistant of uniform distribution of any of said therapeutic agents throughout the outer ear canal.
What is needed is a composition, process and method for providing a barrier upon the epithelial lining of the external auditory canal so as to protect same from the above-described deleterious effects of water and water-born toxins, irritants and antigenic materials. If would be further advantageous if such a composition, process and method was provided so as to decrease the high surface tensions associated with otitis externa so as to promote external auditory canal patency. It would be still further advantageous if a composition and method were provided for delivering therapeutically active agents, effective in the treatment of otitis externa, throughout the epithelial lining of the outer ear while simultaneously reducing the surface tension thereof .